26ga
Tetrameric cystathionine beta-synthase of Mycobacterium tuberculosis bound to O-Benzylhydroxylamine
Structural highlights
FunctionCBS_MYCTU Hydro-lyase catalyzing the first step of the transsulfuration pathway, where the hydroxyl group of L-serine is displaced by L-homocysteine in a beta-replacement reaction to form L-cystathionine, the precursor of L-cysteine (PubMed:35749503). This catabolic route allows the elimination of L-methionine and the toxic metabolite L-homocysteine (PubMed:35749503). Also capable of generating lanthionine and hydrogen sulfide (PubMed:35749503).[1] Publication Abstract from PubMedTuberculosis (TB) remains a major global health threat, with Mycobacterium tuberculosis (Mtb) infecting nearly a quarter of the global population. Drug-resistant TB and HIV-TB co-infections emphasize the need for novel therapeutic approaches targeting essential metabolic pathways. Here, we investigated Mtb cystathionine beta-synthase (MtbCBS), a pyridoxal 5'-phosphate (PLP) dependent enzyme critical for sulfur metabolism and redox regulation, owing to its potential as a therapeutic target. Despite growing efforts to develop novel therapeutics, the widely used inhibitor aminooxy acetic acid (AOAA) is a non-specific inhibitor of all PLP-dependent enzymes, and the precise structural and mechanistic basis for its activity and specificity remains poorly understood. We present the high-resolution cryo-EM structure of full-length tetrameric MtbCBS in complex with AOAA, revealing a stable PLP-inhibitor adduct stabilized by two highly conserved active-site residues, T75 and Q147. This integrated approach employs cryo-EM, molecular dynamics (MD) simulations, Density Functional Theory (DFT) calculations, and comparative inhibition studies to reveal the molecular basis and determinants governing PLP-enzyme MtbCBS inhibition by AOAA. Through molecular mimic studies, we identified precise structural and electronic features of the inhibitor candidate that are critical for inhibition efficiency. These findings provide a mechanistic rationale for MtbCBS inhibition, and the unexplored roles of these key residues can be considered in the design of next-generation inhibitors targeting CBS enzymes implicated in infectious diseases, cancer, and neurological disorders. Molecular insights into inhibitor action on the catalytic activity of Mycobacterium tuberculosis cystathionine beta-synthase enzyme.,Polepalli S, Roy A, Mondal B, Singh A, Dutta S Int J Biol Macromol. 2026 Aug 10;381(Pt 1):154013. doi: , 10.1016/j.ijbiomac.2026.154013. PMID:42575362[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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